A wide variety of anti-metabolites and other compounds have been used in chemotherapy for the treatment of malignancies in humans, with unpredictable records of failure and success. A number of compounds, such as 5-fluorouracil, adriamycin, cytoxan, and prednisone have been extensively used, and a number of other compounds have been shown to exhibit anti-tumor activity. It is understatement to acknowledge that a completely and predictively satisfactory chemotherapeutic agent has not been found. Those compounds currently employed are successful in some cases and not in others, and frequently, if not usually, involve side-effects which range from unpleasant to life-threatening. Accordingly, new compounds with anti-tumor activity, which also may have reduced toxicity, are always of interest.
The variability of effectiveness associated with the nature of the particular disease, and the metabolism of the treated subject, is a result of causes sufficiently obscure, that it appears probable there will be no universally effective single chemotherapeutic agent. Therefore, the interests of the population needing treatment as a whole are best served by providing a spectrum of agents which have the required activity, and exhibit individual differences in metabolic effects.
Adriamycin is a generic name for doxorubicin which, along with its 14-deoxy analog, daunorubicin, is a successful agent in the treatment of a large number of solid tumors and leukemias. Typically, however, the success of specific compounds in this class is not uniform with respect to all patients, and the rate of success is lower with some particular tumor types, such as colon cancer and melanoma. Side effects of treatment with doxorubicin and daunorubicin include damage to the cardiovascular system and symptomatic distress. Thus, a number of analogs to these compounds have been prepared, which are active in a standard screen against mouse leukemia P-388, and exhibit variation in level of side-effects and mode of action.
Summaries of the spectrum of analogs currently available are found in Henry, D. W., Adriamycin, ASC Symposium Series No. 30, Cancer Chemotherapy, American Chemical Society (1976) 15-57; and in Arcamone, F., Doxorubicin, Academic Press, (1981). One analog under trial, AD32, is disclosed in U.S. Pat. No. 4,035,566.
A number of other analogs have been disclosed. U.S. Pat. No. 4,109,076 discloses 5-imino-daunorubicin; its doxorubicin analog is disclosed in Acton, E. M., et al, J Med Chem (1981) 24:669. U.S. Pat. No. 4,301,277 discloses the morpholino analog of daunorubicin, 3'-deamino-3'-(4"-morpholino)daunorubicin; additional analogs of this compound and their properties, as well as those of the 4-methoxy-1-piperidinyl analog, are disclosed in Mosher, C. W., et al, J Med Chem (1982) 25:18-24. 3'-N-alkylated analogs are disclosed in Tong, G. L., et al, J Med Chem (1979) 22:912-918. The N-benzyl and N,N-dibenzyl derivatives are disclosed in U.S. Pat. Nos. 4,177,264 and 4,250,303.
U.S. Pat. No. 4,464,529 discloses additional morpholino analogs bearing a cyano group in the 3-position of the morpholine ring. A continuation-in-part of the original application, upon which the foregoing patent is based, Ser. No. 598,016, filed Apr. 9, 1984, and assigned to the same assignee, incorporated herein by reference, discloses additional permutations of the morpholino-type derivatives of adriamycin-like compounds.